Type 2 diabetes mellitus (T2DM) in middle-aged individuals has been consistently associated with deficits in recent memory, attention, executive function, and cognitive efficiency. Insulin resistance (IR) is a progressive pre-diabetic condition. We have strong preliminary evidence that similar cognitive problems are also present among obese adolescents with IR relative to matched non-insulin resistant groups. The purpose of the proposed study is to rigorously establish the nature of the cognitive impairments present among obese adolescents with IR and by means of a systematic and standardized neuropsychological and MRI-approach to further characterize the brain substrates for those abnormalities. In addition, we propose to ascertain whether, relative to matched lean adolescents, obese adolescents without insulin resistance have detectable cognitive impairments. Obesity and IR are associated with inflammation. Thus, we will also assess whether inflammation mediates some of the associations between IR (and/or obesity) and brain dysfunction in adolescence. We seek to critically examine, in three groups of adolescents, the hypotheses that in insulin resistance there are cross-sectional associations between measures of IR and measures of cognition and structural and functional brain integrity. We propose that obese adolescents with IR will have larger reductions than obese adolescents without IR relative to matched (other than on obesity) lean adolescents. In this effort we will study 180 individuals 16-21 years of age separated into three equal sized groups (obese insulin resistant individuals with normal fasting glucose levels, obese adolescents with normal fasting glucose levels and no evidence of significant insulin resistance, and lean adolescents with normal fasting glucose levels and normal insulin function). The two obese groups will be matched on obesity and, in addition, all three groups will be matched 1:1 on, age, education, ethnicity (race), socio-economic status, and gender. We will ensure that all participants are competent in English. All evaluations will use standardized and reliable methods. The proposed work will provide key data documenting brain involvement in metabolic disorders associated with obesity in childhood, which will serve as the foundation for future work. PUBLIC HEALTH RELEVANCE: There are over 60 million obese individuals in the United States and the rate of obesity is rising at an alarming rate. The rate of overweight and obesity among children stands at over 30%. Obesity leads to insulin resistance, which is a progressive pre-diabetic condition, and there is emerging evidence that both type 2 diabetes and insulin resistance may damage the brain. The goal of this work is to carefully evaluate the nature of the brain abnormalities that may be related to obesity and insulin resistance among adolescents.